Helicobacter pylori is a gram-negative bacterium that lives in the mucus layer of the stomach lining and is the major cause of chronic gastritis and peptic ulcer disease, which is a major risk factor for gastric cancer. The recent realization of the importance of H. pylori as a human pathogen has focused attention on this infectious disease: It is now well established that it is the infection that should be eradicated, not just the symptoms treated. Vaccines composed of whole Helicobacter (either whole-cell sonicates or heat-killed bacterial) alone or in combination with bacterial toxin adjuvant have been shown to provide immunity in several animal models of infection. One major problem with this approach is that factors inherent in H. pylori may cause inflammation and an inappropriate immune response. One such factor is lipopolysaccharide (LPS), which is known to mediate inflammation and induce cytokine release. The structure of the O polysaccharide portion of H. pylori LPS has recently been elucidated for three different strains; each was found to be unique and to terminate in Lewis x and/or Lewis y blood group antigens. H. pylori is the first bacterium found to express these Lewis antigen determinants. Lewis x and Lewis are found on normal gastric tissue but are more abundant on certain tumor cells. Several hypotheses for the role of H. pylori-borne blood group antigens during H. pylori infection can be considered. They may (1) serve as molecular mimics, blinding the host to H. pylori and thereby helping this pathogen to evade the immune system; (2) act as adhesins interacting with cellular receptors on the gastric mucosa; (3) stimulate autoimmune reactions that cause tissue damage and thus contribute to the disease state; or (4) elicit oral tolerance and thus lead to a decreased ability of the host to clear tumors that are also marked by Lewis antigens. None of thee hypotheses is mutually exclusive, nor would any of them fail to contribute to damage to the host. The long-term goal of this new H. pylori research program is to determine the role of Lewis antigens in the pathogenesis and carcinogenic potential of this bacterium. Specifically, a serotyping system for H. pylori based on Lewis antigen expression will be established to type strains from various clinical sources. In addition, H. pylori strains efficient in the production of Lewis antigens will be constructed and evaluated for their pathogenic attributes and their potential as vaccine candidates.